Major histocompatibility complex (MHC) genes control immunological self/nonself recognition and are the most diverse genes known in vertebrates. Despite the central importance of MHC genes to tissue rejection, tumor surveillance, and susceptibility to infectious and autoimmune diseases, the biological significance of MHC diversity is still not understood. Many MHC alleles predispose their bearers to infectious and autoimmue diseases, so what maintains these 'bad genes' in human and animal populations? Here they propose to test the three leading explanations for MHC genetic polymorphisms. (1) MHC diversity can be maintained by selection if MHC heterozygotes are more resistant to infectious diseases. Although there is no evidence for this hypothesis from many experiments testing single infectious agents, the stronger prediction is that heterozygotes should have an advantage during infections by multiple pathogens. The investigators will test this hypothesis by coinfecting MHC-congenic mice with 11 pair-wise combinations of infectious agents that show reciprocal MHC resistance/susceptibility profiles, and compare the resistance of homozygotes and heterozygotes. In addition to measuring pathogen loads, they will assess individual health, vigor, survival, and reproductive success of the coinfected mice in semi-natural enclosures. Preliminary coinfection studies with Salmonella and Theiler's virus have revealed an advantage to heterozygotes as they have an 80% lower (combined) pathogen load than homozygotes. (2) MHC polymorphisms may be the result of rapidly evolving pathogens adapting to MHC-dependent immune recognition, thereby generating selection for rare or new alleles (frequency-dependent selection). The central assumption of this hypothesis asserts that pathogens can evade MHC-dependent immune recognition of their hosts. They will test this assumption by passaging infectious agents through a series of three different MHC congenic strains of mice. Passages will continue for hundreds of pathogen generations to allow time for MHC evasion. Pathogen adaptation to host MHC alleles will be tested by comparing the reproductive output, virulence and related characters of post-and pre passage pathogens. Pathogen evasion of MHC-dependent immunity will be tested for four different infectious agents. The investigators will also test the ability of mouse hepatitis to adapt to different MHC alleles since this is the only pathogen shown to escape MHC-dependent immunity in a natural system. (3) MHC mating preferences may drive MHC-diversity as a mechanism to reduce inbreeding. This assumes that inbreeding is costly, yet no study has experimentally quantified the fitness costs of inbreeding depression for any vertebrate. They have found a 65% decline in fitness for progeny from full-sibling matings when in competition with outbred individuals. They propose to continue their inbreeding studies to determine the fitness consequences of lower levels of inbreeding, which are relevant to medical genetics. These experiments will enable them to determine the nature of selection maintaining MHC diversity. Furthermore, they will continue the integration of the fields of immunology, infectious diseases, ecology, behavior and evolutionary biology.